HIV infection and antiretroviral therapy lead to unfolded protein response activation

Abstract

BackgroundThe unfolded protein response (UPR) is one of the pathways triggered to ensure quality control of the proteins assembled in the endoplasmic reticulum (ER) when cell homeostasis is compromised. This mechanism is primarily composed of three transmembrane proteins serving as stress sensors: PKR-like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme 1 (IRE1). These three proteins’ synergic action elicits translation and transcriptional downstream pathways, leading to less protein production and activating genes that encode important proteins in folding processes, including chaperones. Previous reports showed that viruses have evolved mechanisms to curtail or customize this UPR signaling for their own benefit. However, HIV infection’s effect on the UPR has scarcely been investigated.MethodsThis work investigated UPR modulation by HIV infection by assessing UPR-related protein expression under in vitro and in vivo conditions via Western blotting. Antiretroviral (ARV) drugs’ influence on this stress response was also considered.ResultsIn in vitro and in vivo analyses, our results confirm that HIV infection activates stress-response components and that ARV therapy contributes to changes in the UPR’s activation profile.ConclusionsThis is the first report showing UPR-related protein expression in HIV target cells derived directly from HIV-infected patients receiving different ARV therapies. Thus, two mechanisms may occur simultaneously: interference by HIV itself and the ARV drugs’ pharmacological effects as UPR activators. New evidence of how HIV modulates the UPR to enhance its own replication and secure infection success is also presented.Electronic supplementary materialThe online version of this article (doi:10.1186/s12985-015-0298-0) contains supplementary material, which is available to authorized users.

HIV‐1 Tat‐induced bystander apoptosis in Jurkat cells involves unfolded protein responses

“…Another key ER stress sensor is IRE1, an endonuclease that cleaves a sequence of XBP1 mRNA and its processing into a newly spliced protein that functions as a transcription factor for genes involved in the ER‐resident protein folding and degradation reactions . Similarly to others UPR markers assayed, our findings demonstrate that Tat stimuli also significantly induces expression of the IRE1‐XBP1 axis, in line with the literature . Interestingly, it has been reported that a viral‐induced IRE1 branch activation is involved in both ER homeostatic restoration and cellular survival, and in the triggering of several apoptosis‐regulating mechanisms .…”

“…Many mammalian viruses have evolved to manipulate UPR signalling pathways in host cells to promote viral translation and persistence in infected cells. With specific reference to HIV, it has been shown that UPR‐related proteins are up‐regulated in HIV target cells in vitro or in cells derived from HIV‐infected patients, demonstrating that viral UPR modulation enhances HIV replication and contributes to successful infection . To assess the potential coupling of apoptotic fate and ER stress responses induced by circulant Tat, we performed real‐time mRNA quantification by PCR method to assess the expression levels of crucial ER stress/UPR signature markers and their central downstream effectors.…”

“…16 Similarly to others UPR markers assayed, our findings demonstrate that Tat stimuli also significantly induces expression of the IRE1-XBP1 axis, in line with the literature. 6,39 Interestingly, it has been reported that a viral-induced IRE1 branch activation is involved in both ER homeostatic restoration and cellular survival, and in the triggering of several apoptosis-regulating mechanisms. 34,38,42 This condition is further evidence that the observed Tat-induced increase of XBP1 mRNA happens in parallel with the impairment in cell proliferation at It is well documented that, if UPR-mediated efforts to correct protein-folding fails, apoptosis ensues; in this context, several mechanisms have been proposed to account for the generations of apoptotic signals following ER stress.…”

Heat Shock Protein 90 Facilitates Latent HIV Reactivation through Maintaining the Function of Positive Transcriptional Elongation Factor b (p-TEFb) under Proteasome Inhibition

“…Viral infection will influence cell response and may activate HSF1 and its downstream HSPs (21). Therefore, the J-lat 10.6 cell line, which does not produce viruses, was employed in our following research.…”

Antiretroviral Treatment with Efavirenz Disrupts the Blood-Brain Barrier Integrity and Increases Stroke Severity

“…Epidemiological studies demonstrated that while endothelial dysfunction is reduced following HAART initiation, long term exposure to ARVd leads to the development of vasculopathy, especially with the usage of certain protease inhibitors3435. These conditions could arise from chronic induction of ER stress3637, an increase in local inflammation38, or apoptosis activation39.…”